Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
CA 02269941 1999-04-27
WO 98I22426 PCTISE97101926
1
NEW MANUFACTURING PROCESS OF METOPROLOL
Field of the invention
s The present invention relates to an improved method for the manufacture of
metoproIol
base 1-(isopropylamino)-3-[p-(2-methoxyethyl)-phenoxy]-2-propanol) via the
route of
reacting p-(2-methoxyethyl)-phenol (A) and epichlorohydrin (B) and then
reacting the
obtained 1-(2,3-epoxypropoxy)-4-(2-methoxyethyl)-benzene (AB) with
isopropylamine
(C). The crude metoprolol base is then purified.
~o
Prior art
Chemical Abstracts, vol. 112 ( 1990) abstract no 197820 discloses the reaction
of p-(2-
methoxyethyl)-phenol and epichlorohydrin in the two phase system of water and
organic
i s solvent.
Swedish patents 354 851 and 368 004 disclose the reaction of p-(2-
methoxyethyl)-phenol
and epichlorohydrin where the epichlorohydrin is used not only as a building
block in the
reaction but also as solvent.
zo
Disclosure of the invention
It has now been found that metoprolol can be prepared in a manner that is
fast,
environmentally sound and gives a good yield and high purity using reactants
that are
zs known her se. The difference from the prior art is that the new method uses
no other
solvents than water for the reaction of A and B. From an environmental as well
as an
occupational hazard point of view it is a great advantage to be able to
replace a hazardous
organic solvent with an non-noxious solvent such as water.
3o The method of the invention is illustrated by the reaction scheme below:
CA 02269941 1999-04-27
WO 98I22426 PCT/SE97/01926
2
OH
p-(2-Methoxyethyl)phenol {A)
O
i
O
p CI / \ Epichlorohydrin (B)
Step 1 ii
O
1-(2,3-Epoxypropoxy)-4-
(AB )
/ (2-methoxyethyl)-benzene
~O
Isopropylamine (C)
Step 2 ~ H2N
O N~ 1-Isopropyiamino-3-[p-(2-
OH methoxyethyl)-phenoxy]
2-propanol, metoprolol base
~O
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General example
p-(2-Methoxyethyl)phenol (A) and epichlorohydrin (B, 1.4-2.0 eqv.) are reacted
in water,
at least 1.5 kg, preferably about 2 kg of water per kg of phenol, during the
addition of
s sodium (or potassium) hydroxide solution, (1.3-1.7 eqv.) to form 1-(2,3-
epoxypropoxy)-4-
(2-methoxyethyl)benzene; (p-methoxyethyl-epoxypropoxybenzene). The reaction is
preferably performed at a temperature of 50 - 70 ~C.
The two phases are separated, and the p-methoxyethylepoxy-propoxybenzene is
isolated by
i o distillation under reduced pressure. More particular, the excess of
epichlorohydrin is
evaporated, and the epoxide is distilled under reduced pressure to obtain a
product with a
purity of about 96-98%. If desired, before distilling the main fraction of the
epoxide, a
prefraction/forecut (2-8 %, preferably 4-6 %) thereof could be distilled. The
isolation by
destillation of the epoxide under reduced pressure is an important part of the
process and
is essential for the quality of the end product.
The epoxide is reacted with isopropylamine preferably in isopropyl alcohol to
form
metoprolol base. The amount of isopropylamine in relation to epoxide is at
least 1
equivalent, preferably 3-6 equivalents. The reaction mixture is then treated
in order to
zo eliminate the excess of isopropylamine.
Alternatively, the amination with isopropylamine is carried out in a
pressurized system
without isopropyl alcohol at 70 ~ 10~C at pressures of 2.8-3.2 kg / 275-315
kPa.
2s The resulting metoprolol is dissolved in toluene, isobutyl methyl ketone or
butyl acetate
and extracted with dilute hydrochloric acid or sulphuric acid, preferably at
pH 4-6. The
phases are separated and the chosen solvent with sodium or potassium hydroxide
solution
to adj ust the pH to 11 - 13 is added to the aqueous phase. The two phases are
separated,
and the organic phase is evaporated in vacuo to an oily residue of metoprolol
base which is
3o dissolved in acetone. Purified metoprolol base is then obtained by
conventional means.
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Working example
1-(2,3-epoxypropoxy)-4-(2-methoxyethyl) benzene
s p-(2-Methoxyethyl)phenol (A, - 6,6 mol), epichlorohydrin (B, 1.45 eqv.) and
water (- 2
kg) were combined and the mixture heated to ~ 50~C.
Sodium hydroxide solution (50%; 1.4 eqv.) was added during 3 hours and the
temperature
was elevated to reach approximately 60~C during the addition. Formation of the
title
compound occured during this period.
io
The batch was stirred for another hour at approximately 60~C, then cooled to
approximately 50~C and the phases were separated and the product washed with
water.
The residue was distilled at <_ 190~C and a pressure of __<20 mm Hg and the
distillate was
i s collected. The yield of the title compound was 80% of theory and the
purity was 98%
according to GC analysis.
Metoprolol base
20 1-(2,3-epoxypropoxy)-4-(2-methoxyethyi)benzene (1 kg, 4.8 mol), isopropyl
alcohol (~0.9
kg) and isopropylamine (0.8-1.7 kg, 3-6 eqv.) were mixed and reacted for 2-5
hours at
reflux. Formation of metoprolol base occured during this period.
The reaction mixture was then concentrated at atmospheric pressure until the
inner
is temperature reached 100~C. Water was added to the batch and then distilled
off in vacuo
until the inner temperature reached ~ 100~C to form a concentrate.
The resulting concentrate was diluted with isobutyl methyl ketone (~0.6 kg)
and water
(~2.2 kg), and concentrated sulphuric acid was added, to adjust the pH to 4-6.
CA 02269941 1999-04-27
WO 98I22426 PCT/SE97/01926
After separation, isobutyl methyl ketone {~ 1 kg) was added to the water
layer, and
concentrated sodium hydroxide solution was added to adjust the pH to 13.
The organic layer was concentrated in vacuo at <_80~C, until distillation
ceased, and the
concentrated batch was redissolved in acetone (~1.6 kg) and filtered, to yield
metoprolol
base solution. The assay of metoprolol base in the solution was determined by
titration.
Yield: ~ 1.2 kg metoprolol base { 100 %) ~95 % of theory. The purity of the
metoprolol base
was 96 %.
